An important contributor to asthma development and severity is exposure to airborne particles and pollutants. Particulate matter (PM) emitted by vehicular traffic is especially harmful in asthma by virtue of its initiation of airway and systemic inflammation and its pro-allergic adjuvant function. We have recently identified activation of the Notch pathway as a key mechanism by which PM exacerbate airway inflammation. PM induces the Notch ligand Jagged 1 (Jag1) in antigen presenting cells (APC), most notably CD11chigh lung macrophages, by an aryl hydrocarbon receptor-dependent mechanism. Inhibition of Jagged 1 induction in lung macrophages abrogates the pro-allergic inflammatory effects of PM. Importantly, PM promote airway inflammation in interaction with the human pro-asthmatic IL-4 receptor alpha chain (IL-4R?) variant IL-4R?-R576, which we recently found to promote dual Th2/Th17 airway inflammation by destabilizing allergen-specific induced (i)- Treg cells into Th17 cell like cells. We have also established that Notch signaling in Treg cells negatively affects their regulatory function. Treg cell-specific inhibition of Notch signaling potently suppresses allergic airway inflammation and its exacerbation by PM, indicating that Notch signaling in Treg cells is a common end mechanism in allergic airway inflammation, which may proceed in synergy with IL-4R?-R576. Fundamental questions remain regarding the Notch pathways activated by allergens and PM, including the identity of the Notch receptor(s) and their downstream canonical and non-canonical signaling pathways involved. Also relevant are other cellular substrates involved, including APCs and innate lymphoid cells type 2 (ILC2). Elucidating the interaction of PM with IL-4R?-R576 in promoting asthma morbidity and severity in human subjects is of particular relevance to therapy and prevention. Accordingly, our central hypothesis is that PM promotes allergic airway inflammation by activating a Jagged1-Notch signaling circuit involving APC, ILC2 and particularly Treg cells. We also propose that selective Notch receptors, most notably Notch4 and possibly Notch3, play a cardinal role in this process, and that a key mechanism by which PM worsens inflammation is by destabilizing allergen-specific Treg cells alone and in synergy with IL-4R?-R576. Finally, we propose to leverage existing asthma cohorts to study the interaction of PM, acting via the Notch pathway, and the IL-4R?- R576 allele in driving mixed Th2/Th17 cell inflammation in asthma by promoting the subversion of newly formed induced Treg cells into pathogenic Th17 cells. We will also relate subject PM exposure and IL4R576 allele carriage to the severity of asthmatic symptoms and inflammation. Our studies will help elucidate novel mechanisms fundamental to the biology of allergic airway inflammation and its augmentation by PM, and illuminate novel pathogenic pathways that could be therapeutically targeted in asthmatic subjects.